Novel sulphones for inhibition of gamma secretase

ABSTRACT

The invention provides compounds of formula I:  
                 
which are inhibitors of γ-secretase and hence useful in the treatment or prevention of Alzheimer&#39;s disease.

The present invention relates to a novel class of compounds, theirsalts, pharmaceutical compositions comprising them, processes for makingthem and their use in therapy of the human body. In particular, theinvention relates to novel sulphones which inhibit the processing of APPby γ-secretase, and hence are useful in the treatment or prevention ofAlzheimer's disease.

Alzheimer's disease (AD) is the most prevalent form of dementia.Although primarily a disease of the elderly, affecting up to 10% of thepopulation over the age of 65, AD also affects significant numbers ofyounger patients with a genetic predisposition. It is aneurodegenerative disorder, clinically characterized by progressive lossof memory and cognitive function, and pathologically characterized bythe deposition of extracellular proteinaceous plaques in the corticaland associative brain regions of sufferers. These plaques mainlycomprise fibrillar aggregates of β-amyloid peptide (Aβ). The role ofsecretases, including the putative γ-secretase, in the processing ofamyloid precursor protein (APP) to form Aβ is well documented in theliterature and is reviewed, for example, in WO 01/70677.

There are relatively few reports in the literature of compounds withinhibitory activity towards γ-secretase, as measured in cell-basedassays. These are reviewed in WO 01/70677. Many of the relevantcompounds are peptides or peptide derivatives.

WO 00/50391 discloses a broad class of sulphonamides as modulators ofthe production of β-amyloid, but neither discloses nor suggests thecompounds of the present invention.

The present invention provides a novel class of sulphones which areuseful in the treatment or prevention of AD by inhibiting the processingof APP by the putative γ-secretase, thus arresting the production of Aβ.

According to the present invention there is provided a compound offormula I:

where n is 2, 3 or 4;

-   -   Ar¹ represents phenyl or heteroaryl, either of which bears 0-3        substituents independently selected from halogen, CN, NO₂, CF₃,        GHF₂, OH, OCF₃, C₁₋₄alkoxy or C₁₋₄alkyl which optionally bears a        substituent selected from halogen, CN, NO₂, CF₃, OH and        C₁₋₄alkoxy;    -   Ar² represents phenyl or heteroaryl, either of which bears 0-3        substituents independently selected from halogen, CN, NO₂, CF₃,        CHF₂, OH, OCF₃, C₁₋₄alkoxy or C₁₋₄alkyl which optionally bears a        substituent selected from halogen, CN, NO₂, CF₃, OH and        C₁₋₄alkoxy;    -   R¹ represents C₁₋₄alkyl, or together with R² completes a        pyrrolidine, piperidine or homopiperidine ring;    -   R² represents H or C₁₋₆alkyl which optionally bears a        substituent selected from halogen, CN, NO₂, CF₃, OH and        C₁₋₄alkoxy; or together with R¹ completes a pyrrolidine,        piperidine or homopiperidine ring; or together with R³ completes        a tetrahydroisothiazole-1,1-dioxide ring; and    -   R³ represents phenyl, naphthyl or heteroaryl, any of which may        bear up to 3 substituents selected from halogen, CN, NO₂, CF₃,        CHF₂, OH, OCF₃, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, C₂₋₆acyl,        C₂₋₆acyloxy, C₂₋₆acylamino, amino, C₁₋₄alkylamino,        di(C₁₋₄alkyl)amino or C₁₋₄alkyl which optionally bears a        substituent selected from halogen, CN, NO₂, CF₃, OH and        C₁₋₄alkoxy; or R₃ represents CF₃ or a non-aromatic hydrocarbon        group of up to 6 carbon atoms optionally bearing one substituent        selected from halogen, CN, CF₃, OH, OCF₃, C₁₋₄alkoxy,        C₁₋₄alkoxycarbonyl, C₂₋₆acyl, C₂₋₆acyloxy, C₂₋₆acylamino, amino,        C₁₋₄alkylamino, di(C₁₋₄alkyl)amino or phenyl, naphthyl or        heteroaryl, any of which may bear up to 3 substituents selected        from halogen, CN, NO₂, CF₃, CHF₂, OH, OCF₃, C₁₋₄alkoxy,        C₁₋₄alkoxycarbonyl, C₂₋₆acyl, C₂₋₆acyloxy, C₂₋₆acylamino, amino,        C₁₋₄alkylamino, di(CG-4alkyl)amino or C₁₋₄alkyl which optionally        bears a substituent selected from halogen, CN, NO₂, CF₃, OH and        C₁₋₄alkoxy; or R³ together with R² completes a        tetrahydroisothiazole-1,1-dioxide ring;    -   or a pharmaceutically acceptable salt thereof.

In a particular embodiment of the invention, when n is 2 and R¹ and R³are both CH₃ and R² is H and Ar¹ is 4-chlorophenyl and Ar² is2,5-difluorophenyl, the compound of formula I is in the more polar ofthe two possible diastereomeric forms. A measure of the relativepolarity of the said diastereoisomers is their respective retentiontimes on a HPLC column, the more polar diastereoisomer having the longerretnetion time.

As used herein, the expression “non-aromatic hydrocarbon group” refersto any group consisting of carbon and hydrogen atoms only, but notcomprising an aromatic ring, up to an indicated maximum number of carbonatoms. The term therefore encompasses alkyl, alkenyl, alkynyl,cycloalkyl and cycloalkenyl moieties, singly or in any combination.

As used herein, the expression “C₁-_(x)alkyl” where x is an integergreater than 1 refers to straight-chained and branched alkyl groupswherein the number of constituent carbon atoms is in the range 1 to x.Particular alkyl groups include methyl, ethyl, n-propyl isopropyl andt-butyl. Derived expressions such as “C₂₋₆alkenyl”, “hydroxy-C₁₋₆alkyl”,“heteroarylC₁₋₆alkyl”, “C₂₋₆alkynyl” and “C₁₋₆alkoxy” are to beconstrued in an analogous manner.

The expression “C₂₋₆acyl” as used herein refers to C₁₋₅alkylcarbonylgroups in which the alkyl portion may be straight chain, branched orcyclic, and may be halogenated. Examples include acetyl, propionyl andtrifluoroacetyl.

The expression “heteroaryl” as used herein means a monocyclic system of5 or 6 ring atoms, or fused bicyclic system of up to 10 ring atoms,selected from C, N, O and S, wherein at least one of the constituentrings is aromatic and comprises at least one ring atom which is otherthan carbon. Examples of heteroaryl groups include pyridinylpyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl,oxadiazolyl, triazolyl and thiadiazolyl groups and benzo-fused analoguesthereof. Further examples of heteroaryl groups include tetrazole,1,2,4-triazine and 1,3,5-triazine.

The term “halogen” as used herein includes fluorine, chlorine, bromineand iodine, of which fluorine and chlorine are preferred.

For use in medicine, the compounds of formula I may advantageously be inthe form of pharmaceutically acceptable salts. Other salts may, however,be useful in the preparation of the compounds of formula I or of theirpharmaceutically acceptable salts. Suitable pharmaceutically acceptablesalts of the compounds of this invention include acid addition saltswhich may, for example, be formed by mixing a solution of the compoundaccording to the invention with a solution of a pharmaceuticallyacceptable acid such as hydrochloric acid, sulphuric acid,benzenesulphonic acid, methanesulphonic acid, fumaric acid, maleic acid,succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid,tartaric acid, carbonic acid or phosphoric acid. Alternatively, wherethe compound of the invention carries an acidic moiety, apharmaceutically acceptable salt may be formed by neutralisation of saidacidic moiety with a suitable base. Examples of pharmaceuticallyacceptable salts thus formed include alkali metal salts such as sodiumor potassium salts; ammonium salts; alkaline earth metal salts such ascalcium or magnesium salts; and salts formed with suitable organicbases, such as amine salts (including pyridinium salts) and quaternaryammonium salts.

Where the compounds according to the invention have at least oneasymmetric centre, they may accordingly exist as enantiomers. Where thecompounds according to the invention possess two or more asymmetriccentres, they may additionally exist as diastereoisomers. Unlessexpressly indicated otherwise, it is to be understood that all suchisomers and mixtures thereof in any proportion are encompassed withinthe scope of the present invention.

In the compounds of formula I, n is preferably 2 or 3, most preferably2.

In the compounds of formula I, Ar¹ represents optionally substitutedphenyl or heteroaryl. Typical heteroaryl embodiments of Ar¹ are6-membered, such as optionally substituted pyridyl, in particularoptionally substituted 3-pyridyl. Ar¹ is preferably selected from6-(trifluoromethyl)-3-pyridyl and phenyl groups substituted in the4-position with halogen, methyl or mono-, di- or trifluoromethyl. In apreferred embodiment of the invention Ar¹ represents 4-chlorophenyl. Inanother preferred embodiment Ar¹ represents 4-trifluoromethylphenyl.

Ar² preferably represents optionally substituted phenyl, in particularphenyl bearing 2 or 3 halogen substituents. Ar² is typically selectedfrom phenyl groups bearing halogen substituents (preferably fluorine) inthe 2- and 5-positions or in the 2-, 3- and 6-positions. In a preferredembodiment of the invention, Ar² represents 2,5-difluorophenyl.

In a particular embodiment, Ar¹ is 4-chlorophenyl or4-trifluoromethylphenyl and Ar² is 2,5-difluorophenyl.

In one embodiment of the invention, R¹ represents C₁₋₄alkyl, such asmethyl, ethyl propyl or butyl. Within this embodiment, R¹ is preferablymethyl.

In an alternative embodiment, R¹ and R² complete a pyrrolidine,piperidine or homopiperidine ring, preferably a pyrrolidine orpiperidine ring, and most preferably a piperidine ring. Thus, R¹ and R²together may represent (CH₂)_(m) where m is 1, 2 or 3 such that (n+m) is3, 4 or 5. Within this embodiment, n is preferably 2 and m is preferably1 or 2. Most preferably, n and m are both 2.

When R¹ represents C₁₋₄alkyl, R² represents H or optionally-substitutedC₁₋₆alkyl, or together with R³ completes atetrahydroisothiazole-1,1-dioxide ring. In this embodiment, R² istypically selected from H and methyl, ethyl, propyl or butyl which areoptionally substituted with halogen, OH, CN, methoxy or CF₃, or R²together with R³ represents (CH₂)₃. In this embodiment, preferably R²represents H, methyl or 2,2,2-trifluoroethyl, or together with R³represents (CH₂)₃.

When R² represents H or optionally-substituted C₁₋₆alkyl, or forms aring with R¹, R³ is selected from optionally-substituted phenyl,naphthyl or heteroaryl, CF₃, and optionally-substituted hydrocarbon ofup to 6 carbon atoms. In one embodiment, R³ representsoptionally-substituted phenyl, naphthyl or heteroaryl, preferablyoptionally-substituted phenyl or heteroaryl. When aryl or heteroarylgroups represented by R³ bear more than one substituent, saidsubstituents are preferably halogen atoms (especially chlorine orfluorine) or alkyl groups (especially methyl). Within this embodiment,R³ aptly represents optionally-substituted phenyl, thiophene, quinoline,thiazole, isoxazole or pyrazole. Preferred substituents include halogen(especially chlorine, bromine or fluorine), alkyl (especially methyl),alkoxycarbonyl (such as methoxycarbonyl) and acylamino (such asacetylamino). Preferred examples of aryl or heteroaryl groupsrepresented by R³ include phenyl, 2-thienyl, 3-chloro-2-thienyl,5-chloro-2-thienyl, 3-bromo-2-thienyl, 8-quinolinyl,2-methoxycarbonyl-3-thienyl, 2-acetylamino-4-methylthiazol-5-yl,3,5-dimethylisoxazol-4-yl and 1,3,5-trimethylpyrazol-4-yl.

In an alternative embodiment R³ represents CF₃ or a non-aromatichydrocarbon group of up to 6 carbon atoms which is optionallysubstituted as described previously. When a phenyl, naphthyl orheteroaryl substituent is present, said substituent may itself bear upto 3 substituents as described earlier. Preferably, said phenyl,naphthyl or heteroaryl substituent itself bears at most one substituentthat is other than halogen or alkyl, and most preferably isunsubstituted. Suitable hydrocarbon groups include alkyl, such asmethyl, ethyl, n-propyl, isopropyl or t-butyl, and alkenyl, such asvinyl or allyl. Preferred substituents include halogen (especiallychlorine) and phenyl. Preferred examples of optionally-substitutedhydrocarbon groups represented by R³ include methyl, isopropyl,3-chloropropyl, benzyl and styryl.

In particularly preferred embodiments of the invention, R³ is selectedfrom methyl, isopropyl, 2-thienyl, benzyl and, in combination with R²,(CH₂)₃.

A sub-class of the compounds of the invention are defined by formula II:

where n, Ar¹, Ar², R² and R³ have the same definitions and preferredidentities as before;and pharmaceutically acceptable salts thereof.

Preferably, n is 2 or 3, and most preferably n is 2.

In a first subset of the compounds of formula II, R² represents H,methyl or 2,2,2-trifluoroethyl.

In a second subset of the compounds of formula II, R² and R³ togetherrepresent (CH₂)₃.

It will be readily apparent that in the compounds of formula II thecarbon atom to which Ar² is attached and the carbon atom to which themethyl group is attached are chiral centres, giving rise to twodiastereomeric and four enantiomeric forms. All these possible isomericforms, singly or in mixtures of any proportion, are within the scope ofthe invention. However, when n is 2 and R² is H and R³ is CH₃ and Ar¹ is4-chlorophenyl and Ar² is 2,5-difluorophenyl, the more polar of the twodiastereomeric forms is preferred. This preferred diastereoisomer existsin two entantiomeric forms, and that which elutes second under theconditions described in example 1 is preferred.

A second subclass of the compounds of the invention are defined byformula III:

where m, Ar¹ and Ar² have the same definitions and preferred identitiesas before, and R^(3a) represents R³ which does not form a ring with R²;and pharmaceutically acceptable salts thereof.

Preferably m is 2.

In a preferred subset of the compounds of formula III, R^(3a) is methyl,CF₃, 2-thienyl or 3-chloro-2-thienyl.

Examples of individual compounds in accordance with formula I areprovided in the Examples section appended hereto.

The compounds of formula I have an activity as modulators of theprocessing of APP by γ secretase.

The invention also provides pharmaceutical compositions comprising oneor more compounds of formula I or the pharmaceutically acceptable saltsthereof and a pharmaceutically acceptable carrier. Preferably thesecompositions are in unit dosage forms such as tablets, pills, capsules,powders, granules, sterile parenteral solutions or suspensions, meteredaerosol or liquid sprays, drops, ampoules, transdermal patches,auto-injector devices or suppositories; for oral, parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. For preparing solid compositions such astablets, the principal active ingredient is mixed with a pharmaceuticalcarrier, e.g. conventional tableting ingredients such as corn starch,lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate,dicalcium phosphate or gums or surfactants such as sorbitan monooleate,polyethylene glycol, and other pharmaceutical diluents, e.g. water, toform a solid preformulation composition containing a homogeneous mixtureof a compound of the present invention, or a pharmaceutically acceptablesalt thereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective unit dosage forms such as tablets,pills and capsules. This solid preformulation composition is thensubdivided into unit dosage forms of the type described above containingfrom 0.1 to about 500 mg of the active ingredient of the presentinvention. Typical unit dosage forms contain from 1 to 250 mg, forexample 1, 2, 5, 10, 25, 50, 100, 200 or 250 mg, of the activeingredient. The tablets or pills of the novel composition can be coatedor otherwise compounded to provide a dosage form affording the advantageof prolonged action. For example, the tablet or pill can comprise aninner dosage and an outer dosage component, the latter being in the formof an envelope over the former. The two components can be separated byan enteric layer which serves to resist disintegration in the stomachand permits the inner component to pass intact into the duodenum or tobe delayed in release. A variety of materials can be used for suchenteric layers or coatings, such materials including a number ofpolymeric acids and mixtures of polymeric acids with such materials asshellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil or coconut oil as well as elixirs and similarpharmaceutical vehicles. Suitable dispersing or suspending agents foraqueous suspensions include synthetic and natural gums such astragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, poly(vinylpyrrolidone) or gelatin.

The present invention also provides a compound of formula I or apharmaceutically acceptable salt thereof for use in a method oftreatment of the human body. Preferably the treatment is for a conditionassociated with the deposition of β-amyloid. Preferably the condition isa neurological disease having associated β-amyloid deposition such asAlzheimer's disease.

The present invention further provides the use of a compound of formulaI or a pharmaceutically acceptable salt thereof in the manufacture of amedicament for treating or preventing Alzheimer's disease.

The present invention further provides a method of treatment of asubject suffering from or prone to a condition associated with thedeposition of β-amyloid which comprises administering to that subject aneffective amount of a compound according to formula I or apharmaceutically acceptable salt thereof. Preferably the condition is aneurological disease having associated P-amyloid deposition such asAlzheimer's disease.

For treating or preventing Alzheimer's Disease, a suitable dosage levelis about 0.01 to 250 mg/Kg per day, preferably about 0.10 to 100 mg/Kgper day, especially about 1.0 to 50 mg/Kg, and for example about 10 to30 mg/Kg of body weight per day. Thus, a dose of about 500 mg per personper day may be considered. The compounds may be administered on aregimen of 1 to 4 times per day. In some cases, however, dosage outsidethese limits may be used.

Compounds of formula I in which R² does not form a ring with R³ may beprepared by reaction of an amine (IV) with R^(3a)—SO₂Cl:

where R^(2a) represents R² which does not complete a ring with R³, andn, Ar¹, Ar², R¹ and R^(3a) have the same meanings as before. Thereaction may be carried out at ambient temperature in an aprotic solventsuch as dichloromethane in the presence of a base such as pyridine.

Compounds of formula I in which R² and R³ together complete atetrahydroisothiazole-1,1-dioxide ring may be prepared by reaction of anamine IV in which R^(2a) is H with L-(CH₂)₃—SO₂Cl, where L represents aleaving group such as halogen, followed by intramolecular alkylation ofthe resulting sulphonamide nitrogen. Said alkylation may be carried outin refluxing toluene in the presence of sodium hydride.

Amines of formula IV in which R^(2a) is H may be prepared by reductionof nitrites V:

where n, Ar¹, Ar² and R¹ have the same meanings as before. The reductionmay be carried out using borane in THF at 50° C.

The nitrites of formula V may be prepared by alkylation of sulphones VIwith electrophiles VII:

where L, n, Ar¹, Ar² and R¹ have the same meanings as before.

The nitrites V in which n is 2 are more easily prepared by addition ofsulphones VI to cyanoalkenes VIII:

where R¹ has the same meaning as before. The reaction may be carried outin THF at 0° C. in the presence of sodium hydride.

The sulphones VI are prepared as described in U.S. 2003/0114496 A1.

Amines of formula IV in which R^(2a) is alkyl may be prepared byN-alkylation of the corresponding primary amines IV in which R^(2a) isH. Alternatively, the nitrites V may be converted to the correspondingaldehydes by treatment with diisobutylaluminium hydride followed byhydrolysis, and the aldehydes reacted with R^(2a)NH₂ and sodiumtriacetoxyborohydride. The reaction with DIBAL is typically carried outat −40° C. in dichloromethane, and the second step at ambienttemperature in dichloromethane in the presence of acetic acid.

Amines of formula IV in which R¹ and R^(2a) complete a ring areavailable by reaction of a mesylate of formula XII with the carbanionderived from a sulphone VI:

where BOC represents t-butoxycarbonyl, Ms represents methanesulphonyland R¹ and R^(2a) complete a ring, followed by removal of the BOCprotecting group. The carbanion is formed by treating VI with sodiumhydride in THF at 0° C., and is typically reacted with the mesylate insitu in refluxing THF.

Where they are not commercially available, the starting materialsR^(3a)—SO₂Cl, VII, VIII, X, XI and XII may be prepared by methods knownto those skilled in the art. It will also be apparent to those skilledin the art that certain compounds in accordance with formula I, preparedby the above-described methods, may be converted into other compoundswithin the definition of formula I using standard techniques of organicsynthesis. For example, compounds of formula I in which R² is H may besubjected to N-alkylation to provide corresponding compounds in which R²is alkyl or substituted alkyl.

It will be appreciated that many of the above-described syntheticschemes may give rise to mixtures of stereoisomers. Such mixtures may beseparated by conventional means such as fractional crystallisation andpreparative chromatography.

Certain compounds according to the invention may exist as opticalisomers due to the presence of one or more chiral centres or because ofthe overall asymmetery of the molecule. Such compounds may be preparedin racemic form, or individual enantiomers and diastereoisomers may beprepared either by enantiospecific synthesis or by resolution. The novelcompounds may, for example, be resolved into their component enantiomersby standard techniques such as preparative HPLC, or the formation ofdiastereomeric pairs by salt formation with an optically active acid,such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-1-tartaric acid, followed by fractional crystallisationand regeneration of the free base. The novel compounds may also beresolved by formation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.

During any of the above synthetic sequences it may be necessary and/ordesirable to protect sensitive or reactive groups on any of themolecules concerned. This may be achieved by means of conventionalprotecting groups, such as those described in Protective Groups inOrganic Chemistry, ed. J. F. W. McOmie, Plenum Press, 1973; and T. W.Greene & P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd ed.,John Wiley & Sons, 1999. The protecting groups may be removed at aconvenient subsequent stage using methods known from the art.

An assay which can be used to determine the level of activity ofcompounds of the present invention is described in WO01/70677. Apreferred assay to determine such activity is as follows:

-   1) SH-SY5Y cells stably overexpressing the PβPP C-terminal fragment    SPA4CT, are cultured at 50-70% confluency. 10 mM sodium butyrate is    added 4 hours prior to plating.-   2) Cells are plated in 96-well plates at 35,000 cells/well/100 μL in    Dulbeccos minimal essential medium (DMEM) (phenol red-free)+10%    foetal bovine serum (FBS), 50 mM HEPES buffer (pH7.3), 1% glutamine.-   3) Make dilutions of the compound plate. Dilute stock solution 18.2×    to 5.5% DMSO and 1× final compound concentration. Mix compounds    vigorously and store at 4° C. until use.-   4) Add 10 μL compound/well, gently mix and leave for 18 h at 37° C.,    5% CO₂.-   5) Prepare reagents necessary to determine amyloid peptide levels,    for example by Homogeneous Time Resolved Fluorescence (HTRF) assay.-   6) Plate 160 μL aliquots of HTRF reagent mixture to each well of a    black 96-well HTRF plate.-   7) Transfer 40 μL conditioned supernatant from cell plate to HTRF    plate. Mix and store at 4° C. for 18 hours.-   8) To determine if compounds are cytotoxic following compound    administration, cell viability is assessed by the use of redox dye    reduction. A typical example is a combination of redox dye MTS    (Promega) and the electron coupling reagent PES. This mixture is    made up according to the manufacturer's instructions and left at    room temperature.-   9) Add 10 μL/well MTS/PES solution to the cells; mix and leave at    37° C.-   10) Read plate when the absorbance values are approximately 0.4-0.8.    (Mix briefly before reading to disperse the reduced formazan    product).-   11) Quantitate amyloid beta 40 peptide using an HTRF plate reader.

Alternative assays are described in Biochemistry, 2000, 39(30),8698-8704.

See also, J. Neuroscience Methods, 2000, 102, 61-68.

The Examples of the present invention all had an ED₅₀ of less than 1 μM,typically less than 0.5 μM, in most cases less than 100 nM, and inpreferred cases less than 10 nM, in at least one of the above assays.

The following examples illustrate the present invention.

EXAMPLES

Intermediate A

2-[(4-Chlorobenzenesulfonyl)methyl]-1,4-difluorobenzene

-   -   prepared as described in U.S. 2003/0114496 A1 (page 8,        Intermediate 1).

Example 1 (3RS,4RS)-N-[4-(4-Chlorobenzenesulfonyl)-4-(2,5-difluorophenyl)-3-methylbutyl]-methanesulfonamide

a) To a solution of Intermediate A (20.1 g; 66.6 mmol) in dry THF (200ml) at 0° C. was added sodium hydride (60% dispersion in oil; 3.2 g;79.9 mmol) and the mixture was stirred for 30 minutes. Crotononitrile(8.1 ml; 99.9 mmol) was added slowly and stirring continued for 18 hoursat room temperature. The reaction was quenched with water (200 ml),extracted with ethyl acetate (4×100 ml) and the combined organics weredried (MgSO₄) and concentrated in vacua. The crude residue was purifiedby flash chromatography eluting 5 to 25% ethyl acetate in isohexanes toyield, as a mixture of diastereoisomers,(3RS,4RS)-4-(4-chlorobenzenesulfonyl)-4-(2,5-difluorophenyl)-3-methylbutyronitrileas a cream solid, (14.1 g, 57%).

δ_(H) (360 MHz, CDCl₃) 1.1 and 1.6 (total 3H, d, J=6.7 Hz), 2.21 and2.63 (total 1H, 2×dd, J=7.6, 16.8, and J=3.8, 16.8 Hz), 2.90 and 3.14(total 1H, 2×dd, J=3.7, 16.5 and J=6.4, 16.5 Hz), 3.04-3.09 (1H, m),4.54-4.58 (1H, m), 6.75-6.85 (1H, m), 6.93-7.01 (1H, m), 7.31-7.36 (3H,m), 7.47-7.54 (2H, m).

b) To a solution of (3RS,4RS)-4-(4-chlorobenzenesulfonyl)-4-(2,5-difluorophenyl)-3-methylbutyronitrile(2 g, 5.42 mmol) in THF (30 ml) was added borane (1M solution in THF,6.5 ml, 6.5 mmol) and the mixture was heated at 50° C. for 20 hours. Themixture was cooled to room temperature and quenched with methanol (50ml) and HCl (2M, 5 ml), then heated at reflux for one hour. The cooledreaction mixture was concentrated in vacuo and purified by flashchromatography eluting with 2% to 10% methanol in dichloromethane, togive as a mixture of diastereoisomers (3RS,4RS)-4-(4-chlorobenzenesulfonyl)-4-(2,5-difluorophenyl)-3-methylbutylamineas a white solid (1.7 g, 84%).

δ_(H) (360 MHz, CDCl₃) 1.10 and 1.38 (total 3H, d, J=7.9 Hz), 1.41-1.52(1H, m), 1.63-1.70 and 1.80-1.90 (total 1H, m), 2.60-2.94 (3H, m), 4.46(1H, m), 6.70-6.81 (1H, m), 6.89-6.97 (1H, m), 7.29-7.34 (2H, m),7.42-7.53 (3H, m); m/z (ES⁺) 374 (MH⁺).

c) To (3RS,4RS-4-(4-chlorobenzenesulfonyl)-4-(2,5-difluorophenyl)-3-methylbutylamine,(0.1 g, 0.268 mmol), and pyridine (0.045 ml; 0.54 mmol) indichloromethane (5 ml) was added methanesulfonyl chloride (0.03 ml, 0.40mmol) and the mixture was stirred for 24 hours at room temperature. Themixture was diluted with water (5 ml), the phases were separated, andthe organic layer was washed with brine, (5 ml), dried (MgSO₄) andevaporated under reduced pressure. The crude product was purified bypreparative HPLC to yield the title compound as a white solid (50 mg,42%).

Diastereoisomers were separated by preparative HPLC (Supelcosil™ABZ+plus column (100×212 mm) with a mobile phase of 50% acetonitrile:50%(0.1% TFA) water) and then into the single enantiomers of the more polardiastereoisomer pair by chiral preparative HPLC (chiral OJ column(250×21 mm) with a mobile phase of 70% ethanol: 30% iso-hexane, flowrate 4.5 ml/min).

First to elute (Diastereoisomer 1)—δ_(H) (400 MHz, DMSO-d) 0.85-0.89(1H, m), 1.25 (3H, d, J=6.6 Hz), 1.53-1.56 (1H, m), 2.71-2.74 (1H, m),2.81 (3H, s), 2.89-2.96 (2H, m), 4.70 (1H, d, J=8.8 Hz), 6.91 (1H, t,J=8.8 Hz), 7.04-7.09 (1H, m), 7.18-7.21 (1H, m), 7.36 (1H, broad s),7.54-7.62 (4H, m); m/z (ES+) 452 (MH+).

Second to elute (Diastereoisomer 2)—δ_(H) (400 MHz, DMSO-d₆), 0.85-0.87(1H, m), 0.99 (3H, d, J=6.7 Hz), 1.28-1.40 (1H, m), 2.81-2.82 (1H, m),2.89 (3H, s), 2.97-3.06 (2H, m), 4.76 (1H, d, J=6.6 Hz), 7.02 (1H, m),7.10-7.14 (1H, m), 7.21-7.25 (1H, m), 7.38-7.42 (1H, m), 7.57-7.62 (2H,m), 7.62-7.65 (2H, m); m/z (ES+) 452 (MH+).

First to elute (Enantiomer 1)—δ_(H) (400 MHz, CDCl₃) 0.87-0.92 (1H, m),1.26 (3H, d, J=7.6 Hz), 1.26-1.44 (1H, m), 2.83-2.86 (1H, m), 2.94 (3H,s), 3.11-3.17 (1H, m), 3.23-3.27 (1H, m), 4.48 (1H, d, J=7.8 Hz),6.77-6.83 (1H, m), 6.93-6.98 (1H, m), 7.32-7.35 (2H, m), 7.44 (1H, broads), 7.49-7.53 (2H, m); m/z (ES+) 452 (MH+).

Second to elute (Enantiomer 2)—8H (400 MHz, CDCl₃) 0.87-0.91 (1H, m),1.27 (3H, d, J=7.6 Hz), 1.29-1.44 (1H, m), 2.79-2.87 (1H, m), 2.94 (3H,s), 3.11-3.16 (1H, m), 3.23-3.26 (1H, m), 4.48 (1H, d, J=6.9 Hz),6.77-6.83 (1H, m), 6.94-6.97 (1H, m), 7.33-7.35 (2H, m), 7.44 (1H, broads), 7.69-7.71 (2H, m), m/z (ES+) 452 (MH+).

Examples 2-13 were prepared by the procedure of Example 1, using theappropriate sulfonyl chloride in Step (c):

Example 2 (3RS,4RS)-N-[4-(4-chlorobenzenesulfonyl)-4-(2,5-difluorophenyl)-3-methylbutyl]-thiophene-2-sulfonamide

m/z (ES+) 520 (MH+).

Example 3 (3RS 4RS)-N-[4-(4-chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-3-methyl-butyl]-isopropylsulfonamide

m/z (ES+) 478 (MH+).

Example 4 (3RS,4RS)-N-[4-(4-Chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-3-methyl-butyl]-phenylmethanesulfonamide

m/z (ES+) 528 (MH+).

Example 5 (3RS, 4RS)-N-[4-(4-chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-3-methyl-butyl]-quinoline-8-sulfonamide

m/z (ES+) 564 (MH+).

Example 6 (3RS, 4R)-N-[4-(4-Chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-3-methyl-butyl]-phenylsulfonamide

m/z (ES+) 515 (MH+).

Example 7 (3RS,4RS)-Methyl-[4-(4-chloro-benzenesulfonyl)-4-(2.5-difluoro-phenyl)-3-methyl-butylsulfamoyl]-thiophene-2-carboxylate

m/z (ES+) 578 (MH+).

Example 8 (3RS 4RS)-N-{2-[4-(4-Chlorobenzenesulfonyl)-4-(2,5-difluorophenyl)-3-methylbutylsulfamoyl]-4-methylthiazol-5-yl}acetamide

m/z (ES+) 593 (MH+).

Example 9 (3RS,4RS)-N-[4-(4-chlorobenzenesulfonyl)-4-(2,5-difluorophenyl)-3-methylbutyl]-5-chlorothiophene-2-sulfonamide

m/z (ES+) 554 (MH+).

Example 10 (3RS,4RS)-N-[4-(4-chlorobenzenesulfonyl)-4-(2,5-difluorophenyl)-3-methylbutyl]-3,5-dimethylisoxazole-4-sulfonamide

m/z (ES+) 533 (MH+).

Example 11 (3RS,4RS)-N-[4-(4-chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-3-methyl-butyl]-2-phenylethenesulfonamide

m/z (ES+) 540 (MH+).

Example 12 (3RS4RS)-N-[4-(4-chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-3-methyl-butyl]-5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonamide

m/z (ES+) 566 (MH+).

Example 13 (3RS,4RS)-N-[4-(4-chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-3-methyl-butyl]-4-chlorobenzenesulfonamide

m/z (ES+) 548 (MH+).

Example 14 (3RS4RS)-2-[4-(4-Chlorobenzenesulfonyl)-4-(2,5-difluorophenyl)-3-methylbutyl]-isothiazolidine1,1-dioxide

(a) (3RS,4RS)-N-[4-(4-Chlorobenzenesulfonyl-4-(2,5-difluorophenyl)-3-methylbutyl]-3-chloropropane-1-sulfonamidewas prepared from (3RS,4RS)-4-(4-chlorobenzenesulfonyl)-4-(2,5-difluorophenyl)-3-methylbutylamineand 3-chloropropylsulfonyl chloride as in example 1.

m/z (ES+) 514 (MH+).

(b) The aforementioned 3-chloropropanesulfonamide, (0.12 g, 0.24 mmol)in anhydrous toluene (10 ml) was treated with sodium hydride (0.011 g,0.29 mmol) and the mixture heated at reflux for 96 hours. After cooling,dilution with water (30 ml) and extraction with ethyl acetate (3×30 ml),the combined organic fractions were washed with brine, dried (MgSO₄) andevaporated under reduced pressure. The residue was purified by flashchromatography eluting with 10% to 25% ethyl acetate in isohexane togive as a mixture of diastereoisomers the title compound as a colourlesssolid (47 mg, 41%).

δ_(H) (400 MHz, CDCl₃) 0.85-0.90, 1.32-1.38 (1H, m), 1.05 and 1.26(total 3H, d, J=7.0 Hz), 1.62-1.69 (1H, m), 2.08-2.23 (1H, m), 2.35-2.39(2H, m), 2.85-2.98 (1H, m), 3.08-3.24 (4H, m), 3.26-3.46 (1H, m),4.47-4.54 (1H, m), 6.75-6.78 (1H, m), 6.89-6.92 (1H, m), 7.30-7.34 (2H,m), 7.41-7.52 (3H, m); m/z (ES+) 478 (MH+).

Example 15 (3RS,4RS)-N-[4-(4-Chloro-benzenesulfonyl)-4-(2,5-difluoro-phenyl)-3-methyl-butyl]-N-methyl-methanesulfonamide

a) DIBAL (26.46 ml of a 1M solution in toluene) was added dropwise to asuspension of (3RS,4RS)-4-(4-chlorobenzenesulfonyl)-4-(2,5-difluorophenyl)-3-methylbutyronitrile(4.67 g, 1.26 mmol) in dichloromethane (10 ml) at −40° C. and under N₂.The mixture was stirred for one hour at −40° C. and was then quenchedwith a saturated aqueous solution of ammonium chloride (20 ml). Thephases were separated and the organic phase dried (Na₂SO₄) andevaporated under reduced pressure to give as a mixture ofdiastereoisomers (3RS,4RS)-4-(4-chlorobenzenesulfonyl)-4-(2,5-difluorophenyl)-3-methylbutyraldehydeas a yellow oil which was used in the next step without furtherpurification (4.6 g, quantitative).

δ_(H) (360 MHz, CDCl₃) 1.20 and 1.37 (total 3H, d, J=6.6 Hz), 1.60-1.75(2H, m), 3.09-3.45 (2H, m), 4.82-5.12 (1H, m), 7.10-7.14 (1H, m),7.26-7.29 (1H, m), 7.49-7.52 (1H, m), 7.65-7.71 (2H, m), 7.77-7.87 (2H,m).

b) To the aldehyde from Step (a) (0.55 g, 1.47 mmol) and methylamine (2Msolution in THF, 1.48 ml, 2.95 mmol) in dry dichloromethane (5 ml) wasadded acetic acid (0.5 ml) followed by sodium triacetoxyborohydride(0.63 g, 2.95 mmol). The mixture was stirred at room temperature for 16hours before quenching with saturated aqueous sodium bicarbonatesolution (10 ml) and separating the phases. The organic phase was dried(MgSO₄) and evaporated under reduced pressure to yield as a mixture ofdiastereoisomers (3RS,4RS)-N-methyl-[4-(4-chlorobenzenesulfonyl)-4-(2,5-difluorophenyl)-3-methyl-butyl]amineas a gummy yellow solid, which was carried on to the next stage withoutfurther purification.

δ_(H) (400 MHz, CDCl₃) 0.90-0.94, 1.29-1.33 (1H, m; m), 1.07 and 1.35(total 3H, d, J=6.8 Hz), 1.48-1.57 (1H, m), 2.36 and 2.42 (total 3H, s),2.58-2.92 (3H, m), 4.46-4.57 (1H, m), 6.72-6.80 (1H, m), 6.90-6.94 (1H,m), 7.26-7.34 (2H, m), 7.40-7.54 (3H, m); m/z (ES+) 388 (MH+).

c) To the amine from Step (b) (0.116 g, 0.3 mmol) in dry dichloromethane(5 ml) was added pyridine (0.060 ml, 0.75 mmol), followed bymethanesulfonyl chloride (0.035 ml, 0.45 mmol), and the mixture wasstirred at room temperature for 48 hours. After dilution with water (20ml) and extraction with ethyl acetate (3×20 ml), the combined organicfractions were washed with brine, dried (MgSO₄ and evaporated underreduced pressure. The residue was purified by flash chromatographyeluting with 10% to 30% ethyl acetate in iso-hexane to give as a mixtureof diastereoisomers the title compound as a colourless oil (35 mg, 25%).

δ_(H) (360 MHz, CDCl₃) 1.45-1.50 (1H, m), 1.65 and 1.85 (total 3H, d,J=6.8 Hz), 1.88-1.96 (1H, m), 2.20-2.31 (2H, m), 3.37 (3H, d, J=5.2 Hz),3.41 and 3.48 (total 3H, s), 3.87-3.91 (1H, m), 5.08-5.16 (1H, m),7.32-7.43 (1H, m), 7.48-7.57 (1H, m), 7.89-7.94 (2H, m), 8.01-8.13 (3H,m); m/z (ES+) 466 (MH+).

Example 16 (3RS,4RS)-N-[4-(4-Chlorobenzenesulfonyl)-4-(2,5-difluorophenyl)-3-methyl-butyl]-N-(2,2,2-trifluoroethyl)-methanesulfonamide

-   -   prepared by the procedure of Example 15, using        2,2,2-trifluoroethylamine in Step (b).

The product was purified by flash chromatography, eluting with 7% to 20%ethyl acetate in isohexane to give as a mixture of diastereoisomers thetitle compound as a colourless solid (59% yield).

δ_(H) (400 MHz, CDCl₃) 1.05 and 1.28 (total 3H, d, J=6.9 Hz), 1.35-1.45and 1.77-1.86 (total 1H, m), 2.08-2.27 (1H, m), 2.74-2.84 (1H, m), 2.93and 3.00 (total 3H, s), 3.44-3.57 (2H, m), 3.75-4.02 (2H, m), 4.47-4.51(1H, m), 6.75-6.82 (1H, m), 6.91-6.98 (1H, m), 7.31-7.34 (2H, m),7.41-7.52 (3H, m); m/z (ES+) 534 (MH+).

Example 17(RS)-4-[(4-Chlorobenzenesulfonyl)-(2,5-difluoro-henyl)methyl]-1-methanesulfonyl-piperidine

a) Triethylamine (1.4 ml, 10 mmol) was added to a stirred solution oftert-butyl 4-hydroxy-1-piperidine-carboxylate (2.0 g, 9.94 mmol) indichloromethane (40 ml) at −17° C. under nitrogen. Methanesulfonylchloride (0.85 ml, 11 mmol) was added dropwise and the mixture allowedto warm up to room temperature overnight. The reaction mixture wasdiluted with dichloromethane (50 ml) and water (100 ml) was added. Theorganic layer was separated and the aqueous phase was re-extracted withdichloromethane (2×50 ml). The combined organic layers were dried(MgSO₄) and evaporated under reduced pressure. The residue was purifiedby flash chromatography eluting with 50% ethyl acetate in iso hexanes togive tert-butyl 4-methanesulfonyloxy-piperidine-1-carboxylate as acolourless oil (2.47 g, 89%),

δ_(H) (360 MHz, CDCl₃) 1.46 (9H, s), 1.75-1.88 (2H, m), 1.90-2.00 (2H,m), 3.04 (3H, s), 3.25-3.35 (2H, m), 3.65-3.75 (2H, m), 4.88 (1H, m).

b) Sodium hydride (72 mg of a 60% dispersion in mineral oil, 1.8 mmol)was added to a stirred mixture of the mesylate from Step (a) (250 mg,0.895 mmol) and Intermediate A (542 mg, 1.79 mmol) in THF (8 ml) at 0°C. under nitrogen. The mixture was stirred at 0° C. for 1 hour, at roomtemperature for 0.75 hour and under reflux for 72 hours. The mixture waspartitioned between ethyl acetate (10 ml) and water (10 ml) and theorganic layer was separated, washed with brine, dried (MgSO₄) andevaporated under reduced pressure. The residue was purified by flashchromatography, eluting with 20% ethyl acetate in iso-hexane to give(RS)-tert-butyl4-[(4-chlorobenzenesulfonyl)-(2,5-difluorophenyl)methyl]-piperidine-1-carboxylateas a colourless oil (72 mg, 17%).

m/z 386 (MH⁺-BOC).

c) The product of Step (b) (72 mg, 0.15 mmol) in 96% formic acid (2 ml)was stirred at room temperature under nitrogen for 17 hours. Methanolwas added and the mixture was evaporated in vacuo. The residue wasdissolved in a small volume of water (10 ml), basified with saturatedpotassium carbonate solution and extracted with dichloromethane (10 ml).The combined organic extracts were dried (MgSO₄) and evaporated invacuo. This residue was dissolved in dichloromethane (2 ml) undernitrogen and triethylamine (0.029 ml, 0.21 mmol) and methanesulfonylchloride (0.016 ml, 0.21 mmol) were added sequentially. The resultingmixture was stirred at room temperature for 40 hours and thenpartitioned between dichloromethane (10 ml) and water (10 ml). Theaqueous layer was separated and re-extracted with dichloromethane andthe combined organic extracts were dried (MgSO₄) and evaporated invacuo. The residue was purified by flash chromatography, eluting with40% ethyl acetate in isohexane to give the title compound as a whitesolid (37 mg, 58%).

δ_(H) (360 MHz, CDCl₃) 1.39 (1H, m), 1.62-1.76 (2H, m), 2.53-2.83 (7H, mincluding s at δ 2.78), 3.77 (1H, br d, J=12.1 Hz), 3.88 (1H, br d,J=12.3 Hz), 4.48 (1H, br d, J=8.0 Hz), 6.77 (1H, m), 6.95 (1H, m),7.31-7.51 (5H, m); m/z 464 (MH+).

Example 18(RS)-4-[(4-Chlorobenzenesulfonyl)-(2,5-difluorophenyl)-methyl]-1-trifluoromethanesulfonyl-piperidine

(a) A solution of ethyl isonipecotate (20.0 g, 127 mmol) anddi-tertbutyl dicarbonate (29.1 g, 134 mmol) in dry dichloromethane wasstirred at room temperature for 1 hour and the solvent removed underreduced pressure to yield the BOC derivative as a colourless oil (31 g,91%).

δ_(H) (360 MHz, CDCl₃) 1.26 (3H, t, J=7.1 Hz), 1.46 (9H, s), 1.61-1.66(2H, m), 1.85 (2H, m), 2.43 (1H, m), 2.83 (2H, m), 3.95-4.05 (2H, m),4.14 (2H, dd, J=7.1 and 14.2 Hz).

(b) To a solution of the BOC derivative from Step (a) (28 g, 109 mmol)in tetrahydrofuran (100 ml) at −78° C. was added diisobutylaluminiumhydride (1M, 222 ml, 222 mmol) slowly and the reaction mixture stirredfor 2 hours. The mixture was quenched by the slow addition of methanol(60 ml) and allowed to warm to room temperature, poured into ice-cooleddilute hydrochloric acid (1M, 60 ml), and extracted with ethyl acetate(3×40 ml). The combined organic fractions were washed with brine (50ml), dried, and concentrated, to yield tert-butyl4-formyl-piperidine-1-carboxylate (20 g) as a colourless oil which wasused without further purification.

c) To a solution of 2,5-difluoro-1-bromobenzene (24.5 g, 127 mmol) inanhydrous tetrahydrofuran (400 ml) at −78° C. was added n-butyllithium(1.6M, 80 ml, 128 mmol). The solution was stirred for 15 minutestert-butyl-4-formyl-piperidine-1-carboxylate (27.0 g, 127 mmol) addedslowly in THF (50 ml). The mixture was allowed to warm to roomtemperature and stirred for 16 hours, quenched with water (200 ml) andextracted with ethyl acetate (3×150 ml). The combined organics werewashed with water (50 ml), dried (MgSO₄) and concentrated. The residuewas purified by flash chromatography eluting with 3 to 10% ethyl acetatein iso hexanes to yield (RS)-tertbutyl4-[(2,5-difluorophenyl)-hydroxymethyl]-piperidine-1-carboxylate as acolourless oil (14 g, 34%).

δ_(H) (360 MHz, CDCl₃) 1.12-1.45 (3H, m), 1.44 (9H, s), 1.79-1.90 (2H,m), 2.06 (1H, m), 2.55-2.70 (2H, m), 4.09-4.15 (2H, m), 4.77 (1H, m),6.95-6.99 (2H, m), 7.15 (1H, m).

d) To a solution of(RS)-tert-butyl-4-[(2,5-difluorophenyl)-hydroxymethyl]-piperidine-1-carboxylate(1.0 g, 3.1 mmol), and bis(4-chlorophenyl)disulfide (1.7 g, 6.1 mmol) inpyridine (10 ml) at room temperature was added tri-n-butylphosphine (1.2g, 6.1 mmol) and the mixture was stirred at room temperature for 48hours. The solvent was removed, and the residue taken into ethyl acetate(30 ml) and washed with hydrochloric acid (2N, 10 ml) water (10 ml),dried MgSO₄) and evaporated under reduced pressure. The residue purifiedby flash chromatography eluting with 5 to 20% ethyl acetate inisohexanes to yield (RS)-tert-butyl4-[(4-chlorobenzenesulfanyl)-(2,5-difluorophenyl)-methyl]-piperidine-1-carboxylateas an oil (1.1 g, 65%).

δ_(H) (360 MHz, CDCl 1.15 (1H, m), 1.30-1.40 (1H, m), 1.44 (9H, s), 1.46(1H, m), 1.85-1.95 (1H, m), 2.15-2.20 (1H, m), 2.55-2.80 (2H, m),4.00-4.20 (2H, m), 4.31 (1H, d, J=8.8 Hz), 6.86-6.90 (2H, m), 7.05-7.15(5H, m).

e) To a solution of the sulfide from Step (d) (1.1 g, 2.4 mmol) indichloromethane (25 ml) was added mCPBA (50%, 2.1 g, 6.1 mmol), and themixture stirred at room temperature for 16 hours. A saturated aqueoussolution of sodium sulfite (20 ml) was added, the organic phases wereseparated and washed with water (10 ml) dried (MgSO₄) and evaporatedunder reduced pressure. The residue was purified by flash chromatographyeluting with 10% ethyl acetate in isohexanes to give (RS)-tert-butyl4-[(4-chlorobenzenesulfonyl)-(2,5-difluorophenyl)-methyl]-piperidine-1-carboxylateas a white solid (0.75 g, 65%).

δ_(H) (360 MHz, CDCl₃) 1.15-1.20 (1H, m), 1.44 (9H, s), 1.45-1.56 (2H,m), 2.35-2.45 (1H, m), 2.65-2.90 (3H, m), 4.00-4.20 (2H, m), 4.45 (1H,m), 6.70-6.78 (1H, m), 6.85-6.95 (1H, m), 7.27 (2H, d, J=8.5 Hz),7.35-7.45 (1H, m), 7.48 (2H, d, J=8.5 Hz).

f) To a solution of (RS)-tert-butyl4-[(4-chlorobenzenesulfonyl)-(2,5-difluorophenyl)-methyl]-piperidine-1-carboxylate(0.75 g, 1.5 mmol) in dichloromethane (5 ml) was added trifluoroaceticacid (5 ml) and the mixture was stirred at room temperature for 30minutes. The mixture was washed with sodium hydroxide solution (1N, 5ml), water (5 ml), dried (MgSO₄) and evaporated under reduced pressureto yield(RS)-4-[(4-chlorobenzenesulfonyl)-(2,5-difluorophenyl)methyl]-piperidineas a white solid (0.5 g, 83%).

δ_(H) (360 MHz, CDCl₃) 1.47-1.70 (2H, m), 1.85-1.95 (2H, m), 2.65-2.95(4H, m), 3.27-3.44 (2H, m), 4.48 (1H, td, J=8.5 Hz), 6.72-6.76 (1H, m),6.88-6.96 (1H, m), 7.31 (2H, d, J=8.6 Hz), 7.37 (1H, m), 7.48 (2H, d,J=8.6 Hz).

g) To a solution of the piperidine from Step (f) (0.1 g, 0.26 mmol) andtriethylamine (0.036 ml, 0.26 mmol) in dichloromethane (3 ml) at −78° C.was added trifluoromethanesulfonic anhydride (0.15 g, 0.32 mmol) and themixture was warmed to −40° C. and stirred at this temperature for 3hours. The reaction was quenched with aqueous citric acid (10% w/v, 5ml) diluted with dichloromethane (20 ml) and washed with water (20 ml),dried (MgSO₄) and evaporated under reduced pressure. The residue waspurified by flash chromatography eluting with 5% ethyl acetate in isohexanes to yield the title compound as a white solid (0.1 g, 84%).

δ_(H) (360 MHz, CDCl₃) 1.30-1.40 (1H, m), 1.65-1.75 (2H, m), 2.55-2.65(1H, m), 2.70-2.80 (1H, m), 3.06-3.20 (2H, m), 3.85-4.05 (2H, m), 4.45(1H, m), 6.70-6.80 (1H, m), 6.90-7.00 (1H, m), 7.31 (2H, d, J=8.6 Hz),7.40 (1H, m), 7.48 (2H, d, J=8.6 Hz).

1. A compound of formula I:

where n is 2, 3 or 4; Ar¹ represents phenyl or heteroaryl, either ofwhich bears 0-3 substituents independently selected from halogen, CN,NO₂, CF₃, CHF₂, OH, OCF₃, C₁₋₄alkoxy or C₁₋₄alkyl which optionally bearsa substituent selected from halogen, CN, NO₂, CF₃, OH and C₁₋₄alkoxy;Ar² represents phenyl or heteroaryl, either of which bears 0-3substituents independently selected from halogen, CN, NO₂, CF₃, CHF₂,OH, OCF₃, C₁₋₄alkoxy or C₁₋₄alkyl which optionally bears a substituentselected from halogen, CN, NO₂, CF₃, OH and C₁₋₄alkoxy; R¹ representsC₁₋₄alkyl, or together with R² completes a pyrrolidine, piperidine orhomopiperidine ring; R² represents H or C₁₋₆alkyl which optionally bearsa substituent selected from halogen, CN, NO₂, CF₃, OH and C₁₋₄alkoxy; ortogether with R¹ completes a pyrrolidine, piperidine or homopiperidinering; or together with R³ completes a tetrahydroisothiazole-1,1-dioxidering; and R³ represents phenyl, naphthyl or heteroaryl, any of which maybear up to 3 substituents selected from halogen, CN, NO₂, CF₃, CHF₂, OH,OCF₃, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, C₂₋₆acyl, C₂₋₆acyloxy,C₂₋₆acylamino, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino or C₁₋₄alkylwhich optionally bears a substituent selected from halogen, CN, NO₂,CF₃, OH and C₁₋₄alkoxy; or R³ represents CF₃ or a non-aromatichydrocarbon group of up to 6 carbon atoms optionally bearing onesubstituent selected from halogen, CN, CF₃, OH, OCF₃, C₁₋₄alkoxy,C₁₋₄alkoxycarbonyl, C₂₋₆acyl, C₂₋₆acyloxy, C₂₋₆acylamino, amino,C₁₋₄alkylamino, di(C₁₋₄alkyl)amino or phenyl, naphthyl or heteroaryl,any of which may bear up to 3 substituents selected from halogen, CN,NO₂, CF₃, CHF₂, OH, OCF₃, C₁₋₄alkoxy, C₁₋₄alkoxycarbonyl, C₂₋₆acyl,C₂₋₆acyloxy, C₂₋₆acylamino, amino, C₁₋₄alkylamino, di(C₁₋₄alkyl)amino orC₁₋₄alkyl which optionally bears a substituent selected from halogen,CN, NO₂, CF₃, OH and C₁₋₄alkoxy; or R³ together with R² completes atetrahydroisothiazole-1,1-dioxide ring; or a pharmaceutically acceptablesalt thereof.
 2. A compound according to claim 1 of formula II:

where n, Ar¹, Ar², R² and R³ are as defined in claim 1; or apharmaceutically acceptable salt thereof.
 3. A compound according toclaim 1 of formula III:

wherein m is 1, 2 or 3; R^(3a) represents R³ which does not form a ringwith R²; and Ar¹, Ar² and R³ are as defined in claim 1; or apharmaceutically acceptable salt thereof.
 4. A compound according toclaim 1 wherein Ar¹ is 4-chlorophenyl or 4-trifluoromethylphenyl and Ar²is 2,5-difluorophenyl.
 5. A pharmaceutical composition comprising acompound according to claim 1, or a pharmaceutically acceptable saltthereof, and a pharmaceutically acceptable carrier. 6-7. (canceled)
 8. Amethod of treatment of a subject suffering from or prone to a conditionassociated with the deposition of P-amyloid which comprisesadministering to that subject an effective amount of a compoundaccording to claim 1 or a pharmaceutically acceptable salt thereof.
 9. Amethod of preparing a compound according to claim 1 in which R² does notform a ring with R³ comprising reaction of an amine (IV) withR^(3a)—SO₂Cl:

where R^(2a) represents R² which does not complete a ring with R³,R^(3a) represents R³ which does not complete a ring with R², and n, Ar¹,Ar², R¹, R² and R³ are as defined in claim
 1. 10. A method of preparinga compound according to claim 1 in which R² and R³ together complete atetrahydroisothiazole-1,1-dioxide comprising reaction of an amine:

where n, Ar¹, Ar² and R¹ are as defined in claim 1, with L-(CH₂)₃—SO₂Clwhere L represents a leaving group, followed by intramolecularalkylation of the resulting sulphonamide nitrogen.